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SAM-e and St John's Wort For Depression

bipolar meds


Too good to be true?

by John McManamy


Sam-e and St John's wort for depression. The success of Prozac and other SSRI antidepressants some 20 years ago inspired the search for their natural equivalents. The answer wasn't long in coming in the form of SAM-e and St John's Wort (SJW), which had been used extensively in Europe for treating depression. Both are available over-the-counter.

The good news is both these agents probably work as well as antidepressants.

The bad news is both these agents probably work as well as antidepressants.

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Sam-e and St John's wort - The Evidence

The only thing predictable about testing any agent to treat "depression" - be it a natural supplement, a talking therapy, or a psychiatric med - is they will all perform marginally better than a placebo at getting about 50 percent of the test subjects about 50 percent better, which tells us next to nothing.

One illustration: A 2002 study published in JAMA found that SJW, Zoloft, and the placebo turned in equally abysmal results (in the 30 percent range), which meant the study was seriously flawed. The study's authors served up ready excuses for Zoloft's poor performance, but were more than willing to leave SJW hanging out to dry.

Otherwise, the SAM-e and SJW studies we have show short-term "success" rates comparable to antidepressants. The trial database is considerably thinner than for antidepressants, but there is enough there to indicate that no surprises are likely.

As for long-term studies, the best data we have is a 2008 study showing an 18 percent rate of relapse/recurrence over six months for those who initially responded to SWJ. This roughly corresponds to findings from antidepressant trials, indicating the value of staying on an agent that works for you, at least for a number of months.

What we don't know is what happens 12 months out. We do know the antidepressant evidence is hardly encouraging. (Only one in four patients in STAR*D got well and stayed well on their antidepressants over 12 months.) Can we infer similar poop-out rates from SAM-e and SJW? No - we need hard evidence. By the same token, however, it is delusional to assume that whatever gets you well will keep you well forever.

The one clear advantage both agents have over antidepressants is their benign side effects profile. This comes in loud and clear from the available clinical trial data, but there is an important caveat or two:

First, as with any antidepressant, SAM-e and SJW have a mania risk. Individuals with bipolar or whose depressions have a highly recurrent pattern need to be careful.

Second, in the regulated world of pharmaceutical meds and medical practice, adverse events from psychiatric meds are far more likely to become known than in the unregulated world of supplements. With prescription meds, patients report back to their doctors. The FDA insists on new warnings on drug labels.

Keep in mind, any decision regarding any agent powerful enough to alter the brain needs to be entered into with the same degree of skepticism and caution that one applies to any psychiatric med. "Natural" does not equate to "harmless."

With either agent, it is important to keep your doctor in the loop.


SAM-e - short for S-adenosylmethionine - is a molecule found in our bodies and is vital to a process called methylation, where one molecule passes a methyl group (one carbon and three hydrogen atoms) to another molecule.

This metabolic pathway involves folate and vitamin B12. Both these deficiencies have been linked to depression. Vitamin B12 converts to methylcobalamin, which is involved in the synthesis of various neurotransmitters.

The major advantage over antidepressants may be faster onset of action (within two weeks), suggested in some studies.

Early studies yielded ambiguous results, owing to the instability of oral preparations. These have improved over the years, but it pays to buy only from a reputable supplier, and buy only enteric coated tablets (which prevents SAM-e from being broken down in the stomach, where it is useless). Don't take the pills out of their containers until you are ready to use them.

St John's Wort

The active ingredients in SJW are hypericin and hyperforin, extracted from the flowering tops of the plant. Hypericin is believed to decrease the production of the stress hormone cortisol via inhibiting cytokine production of interleukin-6. This suggests that the agent may be most effective in treating the stress that triggers depression rather than the depression, itself, or in treating stress-induced depression.

Unfortunately, clinical trials never test for this sort of thing. Instead, what we know about SJW is based on trials for "depression." Not unpredictably, two large trials showed it was something of a wimp for treating major depression (though one of those trials also demonstrated equally bad results for Zoloft). The results are more encouraging for moderate depression.

The main thing to beware of with SJW is its interactions with other meds, including a protease inhibitor used to treat AIDs. SJW is also an inducer of an important metabolic pathway, cytochrome P450, where many prescription drugs are metabolized, including antidepressants and birth control. In other words, your birth control may not work on SJW.

Wrapping Up Sam-e and St John's Wort

SAM-e and SJW may be natural supplements, but in the context of depression it is more helpful to think them as antidepressants. Hence, regard them with the same degree of caution, keep your expectations modest, and use them wisely, as part of a broader wellness strategy.

See also: Supplements, More on Supplements, and Omega-3

This article completely replaces an earlier article, Feb 2, 2011

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